Carcinomas cause millions of deaths annually. For example, lung carcinomas are responsible for the majority of deaths from cancer among men and are overtaking breast carcinomas as the most frequent cause of cancer death among women. Most cases of carcinomas are incurable by chemotherapy and radiation therapy unless radically removed in the early stages of the disease. There is thus a great need for methods of diagnosis and therapy of carcinomas of the breast, colon, ovary and lung, as well as for other malignant neoplasms such as melanomas.
Monoclonal antibodies reactive with carcinoma-associated antigens are known (see, e.g., Papsidero, Semin. Surg. Oncol., 1 (4):171-81 (1985); Schlom et al., Important Adv. Oncol., 170-92 (1985); Allum et al., Surg. Ann., 18:41-64 (1986); Houghton et al., Semin. Oncol. 13 (2):165-79 (1986); Monoclonal Antibodies in Cancer: Advances for Diagnosis and Treatment, Roth (ed.), Futura Publishing, Mt. Kisco, N.Y. (1986); and Cancer Diagnosis In Vitro Using Monoclonal Antibodies, Kupchik (ed.) Marcel Dekker, Inc., New York, (1988)).
Most of the known monoclonal antibodies are reactive with several types of human carcinomas, while a few antibodies react with carcinomas derived from specific organs of the body, e.g., lung, breast, ovary, colon, stomach or pancreas. The target antigens are commonly glycoproteins or glycolipids (see, e.g., Hellstrom et al., Cancer Research 46:3917-23 (1986); and Fink et al., Prog. Clin. Pathol., 9:121-33 (1984)). For example, monoclonal antibodies reactive with glycoprotein antigens on specific types of carcinomas include those described in U.S. Pat. No. 4,737,579 (monoclonal antibodies to non-small cell lung carcinomas), U.S. Pat. No. 4,753,894 (monoclonal antibodies to human breast cancer), U.S. Pat. No. 4,579,827 (monoclonal antibodies to human gastrointestinal cancer), and U.S. Pat. No. 4,713,352 (monoclonal antibodies to human renal carcinoma). Some monoclonal antibodies react with high molecular weight antigens which appear to be mucins. For example, monoclonal antibody B72.3 appears to recognize a tumor-associated oncofetal glycoprotein antigen of greater than 1,000 kd molecular weight that is selectively expressed on a number of different carcinomas. Thus, B72.3 has been shown to react with 84% of breast carcinomas, 94% of colon carcinomas, 100% of ovarian carcinomas and 96% of non-small-cell lung carcinomas (see Johnston, Acta Cytol., 1 (5):537-56 (1987) and U.S. Pat. No. 4,612,282, issued to Schlom et al.). Similarly, monoclonal antibody KC-4 recognizes an approximately 400-500 kd protein antigen expressed on a number of carcinomas, such as colon, prostate, lung and breast carcinoma (see U.S. Pat. No. 4,708,930).
Monoclonal antibodies reactive with glycolipid antigens that are believed to be associated with certain tumor cells have also been disclosed. For example, Young et al., J. Exp. Med., 150:1008-19 (1979) disclose the production of two monoclonal antibodies specific for asialo GM.sub.2, a cell surface glycosphingolipid antigen that was established as a marker for BALB/c 3T3 cells transformed by Kirsten murine sarcoma virus. See, also, Kniep et al., J. Immunol., 131 (3):1591-94 (1983) and U.S. Pat. No. 4,507,391 (monoclonal antibody to human melanoma).
In addition, monoclonal antibodies reactive with glycolipid antigens found on specific types of carcinoma cells include those described by Rosen et al., Cancer Research, 44:2052-61 (1984) (monoclonal antibodies to human small cell lung cancer); Varki et al., Cancer Research, 44:681-87 (1984) (monoclonal antibodies to human adenocarcinomas of the lung, stomach and colon and melanoma), and U.S. Pat. No. 4,579,827 (monoclonal antibodies to human colon adenocarcinoma). See, also, Hellstrom et al., Proc. Nat'l. Acad. Sci. USA, 83:7059-63 (1986) which describes the L6 monoclonal antibody that recognizes a carbohydrate antigen expressed on the surface of human non-small cell lung carcinomas, breast carcinomas and colon carcinomas.
Additional monoclonal antibodies exhibiting a reactivity to antigens found on a variety of tumor cells are greatly needed. This is because of the antigenic heterogeneity of most tumors which often necessitates, in diagnosis or therapy, the use of a combination of different monoclonal antibodies directed to the same tumor mass. Furthermore, monoclonal antibodies that display a high degree of reactivity with a wide range of tumors, while showing the absence of or only a very weak reactivity with normal tissues, are not common. Such antibodies would clearly be advantageous.
It is thus apparent that a monoclonal antibody reactive with an antigen expressed at high levels by a variety of tumors may become useful towards an earlier diagnosis of cancers, a better definition of the spread of the cancer, the immunological monitoring of cancer patients, as well as for development of improved methods for therapy of cancers. It is also apparent that monoclonal antibodies to novel cell surface molecules can be used for further definition of such molecules which may be of value for preparing immunogens in the form of cancer vaccines, and which may also have important cellular functions, for example, as receptors of hormones or growth factors or as molecules otherwise involved in intra- and intercellular communication. The antigens may even have enzymatic or growth factor activity by themselves.